SUBCUTANEOUS DELIVERY OF POLYMER CONJUGATES OF THERAPEUTIC AGENTS
The present disclosure provides polymer conjugates comprising a polymer and an agent, the agent linked to the polymer via a linking group containing a cleavable moiety.
1 . A polymer conjugate, the polymer conjugate comprising a water soluble polymer and an agent, the agent linked to the water soluble polymer by a releasable linker, the releasable linker cleavable in a subject and providing a sustained, controllable delivery of the agent over a period of days to weeks.
2 . (canceled)
3 . The polymer conjugate of claim 1 , wherein the agent is useful for the treatment of Parkinson's Disease, a disorder characterized by dopamine insufficiency, a disorder characterized by excessive GABA re-uptake or GABA re-uptake, an anxiety disorder, social anxiety disorder, panic disorder, neuropathic pain, chronic pain, muscle tremors, muscle spasms, seizures, convulsions or epilepsy.
4 . The polymer conjugate of claim 1 , wherein the agent is a dopamine agonist, an adenosine A 2A antagonist, an anticholinergic, a monamine oxidase-B inhibitor, a catechol-O-methyl transferase (COMT) inhibitor or a GABA up-take inhibitor.
5 . The polymer conjugate of claim 1 , wherein the agent is rotigotine, (−)rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5-OH-DPAT, ropinirole, pergolide, cabergoline, bromocriptine.
6 . (canceled)
7 . The polymer conjugate of claim 1 , wherein the agent is trihexyphenidyl, piperidin, hyoscyamine, seligiline, rasgaline, tolcapone, entacapone, caffeine, theophylline, istradefylline or preladenant.
8 . (canceled)
9 . (canceled)
10 . The polymer conjugate of claim 1 , wherein the agent is tiagabine or nipecotic acid.
11 . (canceled)
12 . The polymer conjugate of claim 1 , wherein the poly(oxazoline) polymer has a molecular weight range of 300 Da to 200,000 Da.
13 . The polymer conjugate of claim 1 , wherein the poly(oxazoline) polymer has the formula
wherein
R is an initiating group;
L is a releasable linker containing a cleavable moiety cleavable in a subject and providing a sustained, controllable delivery of the dopamine agonist over a period of days to weeks;
A is an agent;
POZ is a poly(oxazoline) polymer;
n is from 1-1000;
b is from 1-50, provided that b is not greater than n; and
T is a terminating group.
14 . The polymer conjugate of claim 13 , wherein T is Z-B-Q
wherein
Z is S, O, or N;
B is an optional linking group; and
Q is a terminal portion of a terminating nucleophile.
15 . The polymer conjugate of claim 13 , wherein R is hydrogen, alkyl or substituted alkyl.
16 . The polymer conjugate of claim 13 , wherein the cleavable moiety contains at least one ester, carboxylate ester, carbonate ester, carbamate, disulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
17 . The polymer conjugate of claim 13 , wherein L has the structure
wherein
R 3 is a linker linking the triazole moiety to the polymer chain;
R 4 is -R 6 -R 7 -R 8 -;
R 6 is a substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl
R 7 is a group containing at least a portion of the cleavable moiety;
R 8 is absent or is O, S, CR c , or NR c ; and
R c is H or substituted or unsubstituted alkyl.
18 . The polymer conjugate of claim 17 , wherein R 7 is —R a —(O)—R b —, —R a —O—C(O)—R b —, —R a —C(O)—NH—(C 6 H 4 )—O—C(O)—R b —, —R a —C(O)—R b —, —R a —C(O)—O—R b —, —R a —O—CH(OH)—R b —, R a —S—S—R b —, R a —O—P(O)(OR 11 )—R b —, or —R a —C(O)—R b —, wherein R a and R b are each independently absent or substituted or unsubstituted alkyl and R 11 is H or a substituted or unsubstituted C1-C5 alkyl.
19 . The polymer conjugate of claim 17 , wherein R 7 is —R a —C(O)—O—R b — and R a , R b and R 8 are each absent, R 7 is —R a —C(O)—R b —, —R a —O—C(O)—R b —, —R a —CH(OH)—R b — or R a —O—P(O)(OR 11 )—R b —, R a and R b are each absent and R 8 is O, R 7 is —R a —O—C(O)—R b — or —R a —C(O)—R b , R a and R b are each absent and R 8 is NH, or R 7 is R a —S—S—R b —, R a and R b are each absent and R 8 is absent.
20 . The polymer conjugate of claim 17 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —CH 2 —C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH 2 (CH 3 )—C(O)—O— or —CH 2 CH 2 CH 2 —C(O)—O.
21 . The polymer conjugate of claim 17 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —CH 2 —CH 2 —O—C(O), —CH 2 —CH 2 —CH 2 —O—C(O), —CH 2 —CH 2 —CO—NH—(C 6 H 4 )—O—C(O)— or —(CH 2 CH 2 O) d —C(O)—, where d is 1-10.
22 . The polymer conjugate of claim 13 having the structure
wherein
R is an initiating group;
L is a releasable linker containing a cleavable moiety cleavable in a subject and providing a sustained, controllable delivery of the dopamine agonist over a period of days to weeks;
A is an agent;
a is ran which indicates a random copolymer or block which indicates a block copolymer;
o is from 1-50;
m is from 1-1000; and
T is a terminating group.
23 . The polymer conjugate of claim 22 , wherein T is Z-B-Q
wherein
Z is S, O, or N;
B is an optional linking group; and
Q is a terminal portion of a terminating nucleophile.
24 . The polymer conjugate of claim 22 , wherein R is hydrogen, alkyl or substituted alkyl.
25 . The polymer conjugate of claim 22 , wherein the releasable linker contains at least one ester, carboxylate ester, carbonate, ester, carbamate, disulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
26 . The polymer conjugate of claim 22 , wherein L has the structure
wherein
R 3 is a linker linking the triazole moiety to the polymer chain;
R 4 is -R 6 -R 7 -R 8 -;
R 6 is a substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl
R 7 is a group containing at least a portion of the cleavable moiety;
R 8 is absent or is O, S, CR c , or NR c ; and
R c is H or substituted or unsubstituted alkyl.
27 . The polymer conjugate of claim 26 , wherein R 7 is —R a —(O)—R b —, —R a —O—C(O)—R b —, —R a —C(O)—NH—(C 6 H 4 )—O—C(O)—R b —, —R a —C(O)—R b —, —R a —C(O)—O—R b —, —R a —CH(OH)—R b —, R a —S—S—R b —, R a —O—P(O)(OR 11 )—R b —, or —R a —C(O)—R b —, wherein R a and R b are each independently absent or substituted or unsubstituted alkyl and R 11 is H or a substituted or unsubstituted C1-C5 alkyl.
28 . The polymer conjugate of claim 26 , wherein R 7 is —R a —C(O)—O—R b — and R a , R b and R 8 are each absent, R 7 is —R a —C(O)—R b —, —R a —O—C(O)—R b —, —R a —CH(OH)—R b — or R a —O—P(O)(OR 11 )—R b —, R a and R b are each absent and R 8 is O, R 7 is —R a —O—C(O)—R b — or —R a —C(O)—R b , R a and R b are each absent and R 8 is NH, or R 7 is R a —S—S—R b —, R a and R b are each absent and R 8 is absent.
29 . The polymer conjugate of claim 26 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —CH 2 —C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH 2 (CH 3 )—C(O)—O— or —CH 2 CH 2 CH 2 —C(O)—O.
30 . The polymer conjugate of claim 26 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —CH 2 —CH 2 —O—C(O), —CH 2 —CH 2 —CH 2 —O—C(O), —CH 2 —CH 2 —CO—NH—(C 6 H 4 )—O—C(O)— or —(CH 2 CH 2 O) d —C(O)—, where d is 1-10.
31 . The polymer conjugate of claim 23 , wherein the polymer conjugate has structure:
wherein p is an integer from 1 to 18.
32 . (canceled)
33 . The polymer conjugate of claim 23 , wherein the polymer
conjugate has structure:
wherein p is an integer from 1 to 18.
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . (canceled)
41 . (canceled)
42 . (canceled)
43 . (canceled)
44 . (canceled)
45 . The polymer conjugate of claim 1 , wherein water-soluble polymer is poly(oxazoline), poly(5,6-dihydro-4h-1,3-oxazine), poly(ethylene glycol), dextran, dextran modified by oxidation, poly(glycerol), poly(glutamate), poly(hydroxypropylmethacrylate), poly(glycosaminoglycan), poly(sialic acid), poly(acryloyloxyethylphosphorylcholine) and copolymers of the foregoing.
46 . The polymer conjugate of claim 1 , wherein the water-soluble polymer is poly(oxazoline), poly(ethylene glycol), dextran or dextran modified by oxidation.
47 . The polymer conjugate of claim 1 , wherein the water-soluble polymer is poly(oxazoline).
48 . The polymer conjugate of claim 1 , wherein the poly(oxazoline) contains a pendant group and the agent is linked to the poly(oxazoline) via the pendant group.
49 . The polymer conjugate of claim 1 wherein the poly(oxazoline) contains from 2 to 50 pendant groups and the agent is linked to the poly(oxazoline) via at least a portion of the pendant groups.
50 . The polymer conjugate of claim 1 , wherein the water-soluble polymer is poly(ethylene glycol).
51 . The polymer conjugate of claim 50 , wherein the poly(ethylene glycol) is linear, multi-arm, branched, forked, pendent, or dendritic.
52 . The polymer conjugate of claim 1 , wherein the water-soluble polymer is dextran or dextran modified by oxidation.
53 . (canceled)
54 . (canceled)
55 . A method for treating a disease or condition related to dopamine insufficiency in the peripheral or central nervous system or a disease or condition characterized by excessive GABA re-uptake or GABA re-uptake, the method comprising the step of administering to the subject an amount of a polymer conjugate of claim 1 .
56 . The method of claim 55 , wherein the disease or condition is Parkinson's disease or restless leg syndrome.
57 . (canceled)
58 . The method of claim 55 , wherein the agent is a dopamine agonist, an adenosine A 2A antagonist, an anticholinergic, a monamine oxidase-B inhibitor or a catechol-O-methyl transferase (COMT) inhibitor.
59 . The method of claim 55 , wherein the agent is rotigotine, (−)rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5-OH-DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.
60 . The method of claim 55 , wherein the agent is trihexyphenidyl, piperidin, hyoscyamine, seligiline, rasgaline, tolcapone, entacapone, caffeine, theophylline, istradefylline or preladenant
61 . The method of claim 55 , wherein the water soluble polymer is poly(oxazoline), poly(5,6-dihydro-4h-1,3-oxazine), dextran, dextran modified by oxidation, polyethylene glycol (PEG), poly(hydroxypropylmethacrylate), polyglutamic acid, polylactic-polyglutamic acid mixture, polysialic acid, polycaprolactone, polyvinylpyrrolidone, poly(sialic acid), polyglycosaminoglycan, polyglycerol, poly(acryloyloxyethylphosphorylcholine), and methacrylate-based copolymer with synthetic forms of phosphorylcholine and copolymers of the foregoing.
62 . The method of claim 55 , wherein the water soluble polymer is poly(oxazoline), polyethylene glycol), dextran or oxidized dextran.
63 . The method of claim 55 , wherein the polymer conjugate is administered by subcutaneous administration.
64 . The method of claim 55 , wherein release of the agent is controlled by the nature of the linking group, the nature of the polymer, the nature of the agent, the size of the polymer, the method of delivery or a combination of the foregoing.
65 . The method of claim 55 , wherein the polymer conjugate is a conjugate of any one of claims 13 , 22 , 31 and 33 .
66 . (canceled)
67 . The method of claim 55 , wherein the disease or condition is an anxiety disorder, social anxiety disorder, panic disorder, neuropathic pain, chronic pain, muscle tremors, muscle spasms, seizures, convulsions or epilepsy.
68 . The method of claim 55 , wherein the agent is tiagabine or nipecotic acid.
69 . (canceled)
70 . (canceled)
71 . (canceled)
72 . (canceled)
73 . (canceled)